This invention relates to novel cyclic amine derivatives.
This invention also relates to chemokine receptor antagonists that may be effective as a therapeutic agent and/or preventive agent for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn""s disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis in which tissue infiltration of blood leukocytes, such as monocytes and lymphocytes, play a major role in the initiation, progression or maintenance of the disease.
Chemokines are a group of inflammatory/immunomodulatory polypeptide factors which have a molecular weight of 6-15 kD and are produced by a variety of cell types, such as macrophages, monocytes, eosinophils, neutrophiles, fibroblasts, vascular endotherial cells, smooth muscle cells, and mast cells, at inflammatory sites. The chemokines can be classified into two major subfamilies, the CXC chemokines (or xcex1-chemokines) and CC chemokines (or xcex2-chemokines), by the common location of the four conserved cysteine residues and by the differences in the chromosomal locations of the genes encoding them. The first two cysteines of CXC chemokines are separated by one amino acid and those of CC chemokines are adjacent. For example IL-8 (abbreviation for interleukin-8) is a CXC chemokine, while the CC chemokines include MIP-1xcex1/xcex2 (abbreviation for macrophage inflammatory protein-1xcex1/xcex2), MCP-1 (abbreviation for monocyte chemoattractant protein-1), and RANTES (abbreviation for regulated upon activation, normal T-cell expressed and secreted). There also exist chemokines which do not fall into either chemokine subfamily. They are lymphotactin, which has only two cysteines and defines the C chemokine, and fractalkine that has a chemokine-like domain in the mucin structure in which the first two cysteines are separated by three amino acids and hence defines CX3C chemokine. These chemokines promote chemotaxis, cell migration, increase the expression of cellular adhesion molecules such as integrins, and cellular adhesion, and are thought to be the protein factors intimately involved in the adhesion and infiltration of leukocytes into the pathogenic sites in such as inflammatory tissues (for references, see for example, Vaddi, K., et al., The Chemokine Facts Book, Academic Press, 1997; Chemoattractant Ligand and Their Receptors, Horuk, R., Ed., CRC Press, 1996; Ward, G. W., et al., Biochem. J., 1998, 333, 457; Luster, A. D., New Engl. J. Med., 1998, 338, 436; Baggiolini, M., Nature, 1998, 392, 565; Rollins, B. J., Blood, 1997, 90, 909; Alam, R., J. Allergy Clin. Immunol., 1997, 99, 273; Hancock, W. W., Am. J. Pathol., 1996, 148, 681; Taub, D. D., Cytokine and Growth Factor Rev., 1996, 7, 335; Strieter, R. M., et al., J. Immunol., 1996, 156, 3583; Furie, M. B., et al., Am. J. Pathol., 1995, 146, 1287; Schall, T. J., et al., Current Opinion in Immunology, 1994, 6, 865; Edginton, S. M., Biotechnology, 1993, 11, 676).
For example, MIP-1xcex1 causes a transient increase in intracellular calcium ion concentration levels and induces migration of T lymphocytes, B lymphocytes (see for example, Taub, D. D., et al., Science, 1993, 260, 355; Schall, T. J., et al., J. Exp. Med., 1993, 177, 1821), and eosinophiles (see for example, Rot, A., et al., J. Exp. Med., 1992, 176, 1489), chemotaxis of natural killer cells (see for example, Maghazachi, A. A., et al., J. Immunol., 1994, 153, 4969), expression of integrins (see for example, Vaddi, K., et al., J. Immunol., 1994, 153, 4721), and osteoclast differentiation (see for example, Kukita, T., et al., Lab. Invest., 1997, 76, 399). MIP-1xcex1 a also enhances IgE and IgG4 production in B cells (see for example, Kimata, H., et al., J. Exp. Med., 1996, 183, 2397) and inhibits hematopoietic stem cell proliferation (see for example, Mayani, H., et al., Exp. Hematol., 1995, 23, 422; Keller, J. R., et al., Blood, 1994, 84, 2175; Eaves, C. J., et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 12015; Bodine, D. M., et al., Blood, 1991, 78, 914; Broxmeyer, H. E., et al., Blood, 1990, 76, 1110).
With respect to the activity of MIP-1xcex1 in vivo and its role in the pathogenesis of disease, it has been reported that it is a pyrogen in rabbits (see for example Davatelis, G., et al., Science, 1989, 243, 1066); that MIP-1xcex1 injection into mouse foot pads results in an inflammatory reaction such as infiltration by neutrophils and mononuclear cells (see for example Alam, R., et al., J. Immunol., 1994, 152, 1298); that MIP-1xcex1 neutralizing antibody has an inhibitory effect or a therapeutic effect in animal models of granuloma (see for example Lukacs, N. W., et al., J. Exp. Med., 1993, 177, 1551), asthma (see for example Lukacs, N. W., et al., Eur. J. Immunol., 1995, 25, 245; Lukacs, N. W., et al., J. Immunol., 1997, 158, 4398), multiple sclerosis (see for example Karpus, W. J., et al., J. Immunol., 1995, 155, 5003; Karpus, W. J., et al., J. Leukoc. Biol., 1997, 62, 681), idiopathic pulmonary fibrosis (see for example Smith, R. E., et al., J. Immunol., 1994, 153, 4704; Smith, R. E., Biol. Signals, 1996, 5, 223), acute lung injury (see for example Shanley, T. P., et al., J. Immunol., 1995, 154, 4793; Standiford, T. J., et al., J. Immunol., 1995, 155, 1515), and rheumatoid arthritis (see for example Kasama, T., et al., J. Clin. Invest., 1995, 95, 2868); that coxsackie virus induced myocarditis and herpes stromal keratitis are inhibited in mice with a disrupted MIP-1xcex1 gene (see for example Cook, D. N. et al., Science, 1995, 269, 1583; Tumpey, T. M., et al., J. Virology, 1998, 72, 3705); and that significant expression of MIP-1xcex1 is observed in patients with chronic inflammatory diseases of lung (see for example Standiford, T. J., et al., J. Immunol., 1993, 151, 2852), hypersensitivity pneumonitis (see for example Denis, M., Am. J. Respir. Crit. Care Med., 1995, 151, 164), rheumatoid arthritis (see for example Koch, A. E., et al., J. Clin. Invest., 1994, 93, 921), infectious meningitis (see for example Lahrtz, F., et al., J. Neuroimmunol., 1998, 85, 33), and chronic inflammation of muscle (see for example Adams, E. M., et al., Proc. Assoc. Am. Physicians, 1997, 109, 275). These studies indicate that MIP-1xcex1 is deeply involved in the local attraction of various subtypes of leukocytes and the initiation, progression and maintenance of resulting inflammatory response.
MCP-1 (also known as MCAF (abbreviation for macrophage chemotactic and activating factor) or JE) is a CC chemokine produced by monocytes/macrophages, smooth muscle cells, fibroblasts, and vascular endothelial cells and causes cell migration and cell adhesion of monocytes (see for example Valente, A. J., et al., Biochemistry, 1988, 27, 4162; Matsushima, K., et al., J. Exp. Med., 1989, 169, 1485; Yoshimura, T., et al., J. Immunol., 1989, 142, 1956; Rollins, B. J., et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 3738; Rollins, B. J., et al., Blood, 1991, 78, 1112; Jiang, Y., et al., J. Immunol., 1992, 148, 2423; Vaddi, K., et al., J. Immunol., 1994, 153, 4721), memory T lymphocytes (see for example Carr, M. W., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3652), T lymphocytes (see for example Loetscher, P., et al., FASEB J., 1994, 8, 1055) and natural killer cells (see for example Loetscher, P., et al., J. Immunol., 1996, 156, 322; Allavena, P., et al., Eur. J. Immunol., 1994, 24, 3233), as well as mediating histamine release by basophils (see for example Alam, R., et al., J. Clin. Invest., 1992, 89, 723; Bischoff, S. C., et al., J. Exp. Med., 1992, 175, 1271; Kuna, P., et al., J. Exp. Med., 1992, 175, 489).
In addition, high expression of MCP-1 has been reported in diseases where accumulation of monocyte/macrophage and/or T cells is thought to be important in the initiation or progression of diseases, such as atherosclerosis (see for example Hayes, I. M., et al., Arterioscler. Thromb. Vasc. Biol., 1998, 18, 397; Takeya, M., et al., Hum. Pathol., 1993, 24, 534; Yla-Herttuala, S., et al., Proc. Natl. Acad. Sci. USA, 1991, 88, 5252; Nelken, N. A., J. Clin. Invest., 1991, 88, 1121), rheumatoid arthritis (see for example Koch, A. E., et al., J. Clin. Invest., 1992, 90, 772; Akahoshi, T., et al., Arthritis Rheum., 1993, 36, 762; Robinson, E., et al., Clin. Exp. Immunol., 101, 398), nephritis (see for example Noris, M., et al., Lab. Invest., 1995, 73, 804; Wada, T., at al., Kidney Int., 1996, 49, 761; Gesualdo, L., et al., Kidney Int., 1997, 51, 155), nephropathy (see for example Saitoh, A., et al., J. Clin. Lab. Anal., 1998, 12, 1; Yokoyama, H., et al., J. Leukoc. Biol., 1998, 63, 493), pulmonary fibrosis, pulmonary sarcoidosis (see for example Sugiyama, Y., et al., Internal Medicine, 1997, 36, 856), asthma (see for example Karina, M., et al., J. Invest. Allergol. Clin. Immunol., 1997, 7, 254; Stephene, T. H., Am. J. Respir. Crit. Care Med., 1997, 156, 1377; Sousa, A. R., et al., Am. J. Respir. Cell Mol. Biol., 1994, 10, 142), multiple sclerosis (see for example McManus, C., et al., J. Neuroimmunol., 1998, 86, 20), psoriasis (see for example Gillitzer, R., et al., J. Invest. Dermatol., 1993, 101, 127), inflammatory bowel disease (see for example Grimm, M. C., et al., J. Leukoc. Biol., 1996, 59, 804; Reinecker, H. C., et al., Gastroenterology, 1995, 106, 40), myocarditis (see for example Seino, Y., et al., Cytokine, 1995, 7, 301), endometriosis (see for example Jolicoeur, C., et al., Am. J. Pathol., 1998, 152, 125), intraperitoneal adhesion (see for example Zeyneloglu, H. B., et al., Human Reproduction, 1998, 13, 1194), congestive heart failure (see for example Aurust, P., et al., Circulation, 1998, 97, 1136), chronic liver disease (see for example Marra, F., et al., Am. J. Pathol., 1998, 152, 423), viral meningitis (see forexample Lahrtz, F., et al., Eur. J. Immunol., 1997, 27, 2484), Kawasaki disease (see for example Wong, M.; et al., J. Rheumatol., 1997, 24, 1179) and sepsis (see for example Salkowski, C. A.; et al., Infect. Immun., 1998, 66, 3569). Furthermore, anti-MCP-1 antibody has been reported to show an inhibitory effect or a therapeutic effect in animal models of rheumatoid arthritis (see for example Schimmer, R. C., et al., J. Immunol., 1998, 160, 1466; Schrier, D. J., J. Leukoc. Biol., 1998, 63, 359; Ogata, H., et al., J. Pathol., 1997, 182, 106), multiple sclerosis (see for example Karpus, W. J., et al., J. Leukoc. Biol., 1997, 62, 681), nephritis (see for example Lloyd, C. M., et al., J. Exp. Med., 1997, 185, 1371; Wada, T., et al., FASEB J., 1996, 10, 1418), Asthma (see for example Gonzalo, J.-A., et al., J. Exp. Med., 1998, 188, 157; Lukacs, N. W., J. Immunol., 1997, 158, 4398), atherosclerosis (see for example Guzman, L. A., et al., Circulation, 1993, 88 (suppl.), I-371), delayed type hypersensitivity (see for example Rand, M. L., et al., Am. J. Pathol., 1996, 148, 855), pulmonary hypertension (see for example Kimura, H., et al., Lab. Invest., 1998, 78, 571), and intraperitoneal adhesion (see for example Zeyneloglu, H. B., et al., Am. J. Obstet. Gynecol., 1998, 179, 438). A peptide antagonist of MCP-1, MCP-1(9 -76), has been also reported to inhibit arthritis in the mouse model (see Gong, J.-H., J. Exp. Med., 1997, 186, 131), as well as studies in MCP-1-deficient mice have shown that MCP-1 is essential for monocyte recruitment in vivo (see Lu, B., et al., J. Exp. Med., 1998, 187, 601; Gu, L., et al., Moll. Cell, 1998, 2, 275).
These data indicate that chemokines such as MIP-1xcex1 and MCP-1 attract monocytes and lymphocytes to disease sites and mediate their activation and thus are thought to be intimately involved in the initiation, progression and maintenance of diseases deeply involving monocytes and lymphocytes, such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn""s disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis (see for example Rovin, B. H., et al., Am. J. Kidney. Dis., 1998, 31, 1065; Lloyd, C., et al., Curr. Opin. Nephrol. Hypertens., 1998, 7, 281; Conti, P., et al., Allergy and Asthma Proc., 1998, 19, 121; Ransohoff, R. M., et al., Trends Neurosci., 1998, 21, 154; MacDermott, R. P., et al., Inflammatory Bowel Diseases, 1998, 4, 54). Therefore, drugs which inhibit the action of chemokines on target cells may be effective as a therapeutic and/or preventive drug in the diseases.
Genes encoding receptors of specific chemokines have been cloned, and it is now known that these receptors are G protein-coupled seven-transmembrane receptors present on various leukocyte populations. So far, at least five CXC chemokine receptors (CXCR1-CXCR5) and eight CC chemokine receptors (CCR1-CCR8) have been identified. For example IL-8 is a ligand for CXCR1 and CXCR2, MIP-1xcex1 is that for CCR1 and CCR5, and MCP-1 is that for CCR2A and CCR2B (for reference, see for example, Holmes, W. E., et al., Science 1991, 253, 1278-1280; Murphy P. M., et al., Science, 253, 1280-1283; Neote, K. et al., Cell, 1993, 72, 415-425; Charo, I. F., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2752-2756; Yamagami, S., et al., Biochem. Biophys. Res. Commun., 1994, 202, 1156-1162; Combadier, C., et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494, Power, C. A., et al., J. Biol. Chem., 1995, 270, 19495-19500; Samson, M., et al., Biochemistry, 1996, 35, 3362-3367; Murphy, P. M., Annual Review of Immunology, 1994, 12, 592-633). It has been reported that lung inflammation and granuroma formation are suppressed in CCR1-deficient mice (see Gao, J.-L., et al., J. Exp. Med., 1997, 185, 1959; Gerard, C., et al., J. Clin. Invest., 1997, 100, 2022), and that recruitment of macrophages and formation of atherosclerotic lesion decreased in CCR2-deficient mice (see Boring, L., et al., Nature, 1998, 394, 894; Kuziel, W. A., et al., Proc. Natl. Acad. Sci., USA, 1997, 94, 12053; Kurihara, T., et al., J. Exp. Med., 1997, 186, 1757; Boring, L., et al., J. Clin. Invest., 1997, 100, 2552). Therefore, compound which inhibit the binding of chemokines such as MIP-1xcex1 and/or MCP-1 to these receptors, that is, chemokine receptor antagonist, may be useful as drugs which inhibit the action of chemokines such as MIP-1xcex1 and/or MCP-1 on the target cells, but there are no drugs known to have such effects.
The cyclic amine derivatives provided by the present invention is quite novel. Recently, it has been reported that the diphenylmethane derivatives (WO9724325; Hesselgesser, J., et al., J. Biol. Chem., 1998, 273, 15687), piperidine derivatives (JP9-249566), imidazobenzodiazepine derivatives (JP9-249570), benzazocine derivatives (JP9-255572), tricyclic compounds with cyclic amino group (WO9804554), phenothiazine derivatives (Bright, C., et al., Bioorg. Med. Chem. Lett., 1998, 8, 771), pieprazine derivatives (WO9744329), benzimidazole derivatives (WO9806703), distamycin analogues (Howard, O. M. Z., et al., J. Med. Chem., 1998, 41, 2184), bis-acridine derivatives (WO9830218), spiro-substituted azacycles (WO9825604; WO9825605), substituted aryl piperazines (WO9825617), aminoquinoline derivatives (WO9827815), 3-arylpiperidine derivatives (WO9831364), hexanoicamide derivatives (WO9838167), and other small molecules (WO9744329; WO9802151; WO9804554) have antagonistic activity of chemokine receptor, such as CXCR1, CXCR4, CCR1, CCR2, CCR3, and CCR5. However, these compounds differ from the compound of the present invention.
Therefore, it is an object of the present invention to provide small molecule compound which inhibits the binding of chemokines such as MIP-1xcex1 and/or MCP-1 to their receptors on the target cells.
It is another object of the present invention to establish a method to inhibit the binding to the receptors on the target cells and/or effects on target cells of chemokines such as MIP-1xcex1 and/or MCP-1.
It is an additional object of the present invention to propose a method for the treatment of diseases for which the binding of chemokines such as MIP-1xcex1 and/or MCP-1 to the receptor on the target cell is one of the causes.
As a result of intensive studies, the present inventors discovered that a cyclic amine derivative having a arylalkyl group, its pharmaceutically acceptable c1-C6 alkyl addition salt or its pharmaceutically acceptable acid addition salt has an excellent activity to inhibit the binding of chemokines such as MIP-1xcex1 and/or MCP-1 and the like to the receptor of a target cell, which has led to the completion of this invention.
That is, the present invention is a compound of the formula (I) below: 
a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C1-C6 alkyl addition salt thereof (Invention 1),
wherein R1 is a phenyl group, a C3-C8 cycloalkyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a C1C6 alkyl group, a C3-C8 cycloalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C3-C5 alkylene group, a C2-C4 alkylenoxy group, a C1-C3 alkylenedioxy group, a phenyl group, a phenoxy group, a phenylthio group, a benzyl group, a benzyloxy group, a benzoylamino group, a C2-C7 alkanoyl group, a C2-C7 alkoxycarbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, a C2-C7 N-alkylcarbamoyl group, a C4-C9 N-cycloalkylcarbamoyl group, a C1-C6 alkylsulfonyl group, a C3C8 (alkoxycarbonyl)methyl group, a N-phenylcarbamoyl group, a piperidinocarbonyl group, a morpholinocarbonyl group, a 1-pyrrolidinylcarbonyl group, a divalent group represented by the formula:xe2x80x94NH(Cxe2x95x90O)Oxe2x80x94, a divalent group represented by the formula: xe2x80x94NH(Cxe2x95x90S)Oxe2x80x94, an amino group, a mono (C1-C6 alkyl)amino group, or a di(C1-C6 alkyl)amino group, wherein the substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring is optionally substituted with one or more of a halogen atom, a hydroxy group, an amino group, a trifluoromethyl group, a C1-C6 alkyl group, or a C1-C6 alkoxy group;
R2 is a hydrogen atom, a C1-C6 alkyl group, a C2-C7 alkoxycarbonyl group, a hydroxy group, or a phenyl group, in which the C1-C6 alkyl or phenyl group may be substituted with one or more of a halogen atom, a hydroxy group, a C1-C6 alkyl group, or a C1-C6 alkoxy group, and when j=0, R2 is not a hydroxy group;
j represents an integer of 0-2;
k represents an integer of 0-2;
m represents an integer of 2-4;
n represents 0 or 1;
R3 is a hydrogen atom or a C1-C6 alkyl group optionally substituted with one or two phenyl groups each of which may be substituted with one or more of a halogen atom, a hydroxy group, a C1-C6 alkyl group, or a C1-C6 alkoxy group;
R4 and R5 are the same or different from each other and are a hydrogen atom, a hydroxy group, a phenyl group, or a C1-C6 alkyl group, in which the C1-C6 alkyl group is optionally substituted with one or more of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, a carboxy group, acarbamoyl group, a mercapto group, a guanidino group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a phenyl group optionally substituted with one or more of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a benzyloxy group, a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C2-C7 alkanoyl group, a C2 -C7 alkoxycarbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, a C2-C7 N-alkylcarbamoyl group, a C1 -C6 alkylsulfonyl group, an amino group, a mono (C1-C6 alkyl)amino group, a di(C1-C6 alkyl)amino group, or an aromatic heterocyclic group having 1-3 of heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof and optionally condensed with benzene ring, or R4 and R5 taken together form a 3 to 6 membered cyclic hydrocarbon;
p represents 0 or 1;
q represents 0 or 1;
G is a group represented by xe2x80x94COxe2x80x94, xe2x80x94SO1xe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR7xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CSxe2x80x94NHxe2x80x94, xe2x80x94NR7xe2x80x94SO2xe2x80x94, xe2x80x94SO2xe2x80x94NR7, xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, or xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94, wherein R7 is a hydrogen atom or a C1-C6 alkyl group, or R7 taken together with R5 represents C3-C5 alkylene group;
R6 is a phenyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkenyl group, a benzyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl, benzyl, or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a mercapto group, a cyano group, a nitro group, a thiocyanato group, a carboxy group, a carbamoyl group, a trifluoromethyl group, a C1-C6 alkyl group, a C3-C6 cyclbalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyloxy group, a C1-C6 alkylthio group, a C1-C3 alkylenedioxy group, a phenyl group, a phenoxy group, a phenylamino group, a benzyl group, a benzoyl group, a phenylsulfinyl group, a phenylsulfonyl group, a 3-phenylureido group, a C2-C7 alkanoyl group, a C2-C7 alkoxycarbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, a C2-C7 N-alkylcarbamoyl group, a C1-C6 alkylsulfonyl group, a phenylcarbamoyl group, a N,N-di(C1-C6 alkyl)sulfamoyl group, an amino group, a mono(C1-C6 alkyl)amino group, a di(C1-C6 alkyl)amino group, a benzylamino group, a C2-C7 (alkoxycarbonyl)amino group, a C1-C6 (alkylsulfonyl)amino group, or a bis(C1-C6 alkylsulfonyl)amino group, wherein the substituent for the phenyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring is optionally substituted with one or more of a halogen atom, a cyano group, a hydroxy group, an amino group, trifluoromethyl group, a C1-C6 alkyl group, a C1C6 alkoxy group, a C1-C6 alkylthio group, a mono(C1C6 alkyl)amino group, or a di(C1-C6 alkyl)amino group.
Also the present invention is a method of inhibiting the binding of a chemokine to the receptor of a target cell and/or its action on a target cell using a pharmaceutical preparation containing a therapeutically effective amount of a compound represented by the above formula (I), a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable C1-C6 alkyl addition salt thereof (Invention 2).
Here, the compound represented by the above formula (I) have activities to inhibit the binding of chemokines such as MIP-1xcex1 and/or MCP-1 and the like to the receptor of a target cell and activities to inhibit physiological activities of cells caused by chemokines such as MIP-1xcex1 and/or MCP-1 and the like.
In the above formula (I), R1 is a phenyl group, a C3-C8 cycloalkyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C3-C5 alkylene group, a C2-C4 alkylenoxy group, a C1-C3 alkylenedioxy group, a phenyl group, a phenoxy group, a phenylthio group, a benzyl group, a benzyloxy group, a benzoylamino group, a C2-C7 alkanoyl group, a C2-C7 alkoxycarbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, a C2-C7 N-alkylcarbamoyl group, a C4-C9 N-cycloalkylcarbamoyl group, a C1-C6 alkylsulfonyl group, a C3-C9 (alkoxycarbonyl)methyl group, a N-phenylcarbamoyl group, a piperidinocarbonyl group, a morpholinocarbonyl group, a 1-pyrrolidinylcarbonyl group, a divalent group represented by the formula:xe2x80x94NH(Cxe2x95x90O)Oxe2x80x94, a divalent group represented by the formula: xe2x80x94NH(Cxe2x95x90S)Oxe2x80x94, an amino group, a mono(C1-C6 alkyl)amino group, or a di(C1-C6 alkyl)amino group.
The xe2x80x9cC3-C8 cycloalkyl groupxe2x80x9d for R1 means a cyclic alkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl group, specifically including a cyclopropyl, cyclopentyl, and cyclohexyl group.
The xe2x80x9caromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting, of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereofxe2x80x9d for R1 is specifically, for example, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazinyl, triazolyl, oxadiazolyl (furazanyl), thiadiazolyl group and the like, preferably including a thienyl, furyl, pyrrolyl, isoxazolyl, and pyridyl group.
The xe2x80x9ccondensed ringxe2x80x9d for R1 means a ring obtained by the condensation with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom of a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom and/or a nitrogen atom, at any possible sites, suitably and specifically for example, naphthyl, indolyl, benzofuranyl, benzothienyl, quinolyl, benzimidazolyl, benzoxazolyl, benzotriazolyl, benzoxadiazolyl (benzofurazanyl), and benzothiadiazolyl group.
Among them, a phenyl group and an isoxazolyl group can be listed as a preferred specific example for R1.
The xe2x80x9chalogen atomxe2x80x9d as a substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1 includes a fluorine atom, chlorine atom, bromine atom, and iodine atom, suitably including a fluorine atom, chlorine atom, and bromine atom.
The xe2x80x9cC1-C6 alkyl groupxe2x80x9d as a substituent for R1 means a C1-C6 straight-chain or a branched alkyl group such as a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, 2-methylpentyl, 1-ethylbutyl group, and the like, suitably specifically including a methyl, ethyl, propyl, and isopropyl group.
The xe2x80x9cC2-C6 cycloalkyl groupxe2x80x9d as a substituent for R1 is the same as defined for the aforementioned xe2x80x9cC3-C8 cycloalkyl groupxe2x80x9d for R1, where the same examples can be given for the preferred specific examples.
The xe2x80x9cC2-C6 alkenyl groupxe2x80x9d as a substituent for R1 means a C2-C6 straight-chain or a branched alkenyl group such as a vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 4-pentenyl, 5-hexenyl, 4-methyl-3-pentenyl group, and the like, suitably specifically including a vinyl and 2-methyl-1-propenyl group.
The xe2x80x9cC1-C6 alkoxy groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C1-C6 alkyl group and oxy group, specifically, for example, a methoxy and ethoxy group.
The xe2x80x9cC1-C6 alkylthio groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C1-C6 alkyl group and thio group, specifically, for example, a methylthio and ethylthio group.
The xe2x80x9cC3-C8 alkylene groupxe2x80x9d as a substituent for R1 means the C3-C5 divalent alkylene group such as a trimethylene, tetramethylene, pentamethylene, and 1-methyltrimethylene group, specifically, for example, a trimethylene and a tetramethylene group.
The xe2x80x9cC2-C4 alkylenoxy groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C2-C4 divalent alkylene group and oxy group such as a ethylenoxy (xe2x80x94CH2CH2Oxe2x80x94), trimethylenoxy (xe2x80x94CH2CH2CH2Oxe2x80x94), tetramethylenoxy (xe2x80x94CH2CH2CH2CH2Oxe2x80x94), and 1,1-dimethylethylenoxy (xe2x80x94CH2C(CH3)2Oxe2x80x94) group, specifically, for example, a ethylenoxy and trimethylenoxy group.
The xe2x80x9cC1-C3 alkylenedioxy groupxe2x80x9d as a substituent for R1 means group consisting of C1-C3 divalent alkylene group and two oxy groups such as a methylenedioxy (xe2x80x94OCH2Oxe2x80x94), ethylenedioxy (xe2x80x94OCH2CH2Oxe2x80x94), trimethylenedioxy (xe2x80x94OCH2CH2CH2Oxe2x80x94, and propylenedioxy (xe2x80x94OCH,CH(CH3)Oxe2x80x94) group, specifically, for example, a methylenedioxy and ethylenedioxy group.
The xe2x80x9cC2-C7 alkanoyl groupxe2x80x9d as a substituent for R1 means C2-C7 straight-chain or branched alkanoyl group such as an acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, isobutyryl, 3-methylbutanoyl, 2-methylbutanoyl, pivaloyl, 4-methylpentanoyl, 3,3-dimethylbutanoyl, 5-methylhexanoyl group, and the like, where the preferred and specific example includes an acetyl group.
The xe2x80x9cC2-C7 alkoxycarbonyl groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C1-C6 alkoxy group and carbonyl group, preferably and specifically for example, a methoxycarbonyl and ethoxycarbonyl group.
The xe2x80x9cC2-C7 alkanoyloxy groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C2-C7 alkanoyl group and oxy group, specifically, for example, an acetyloxy group.
The xe2x80x9cC2-C7 alkanoylamino groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C2-C7 alkanoyl group and amino group, specifically, for example, an acetylamino group.
The xe2x80x9cC2-C7 N-alkylcarbamoyl groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C1-C6 alkyl group and carbamoyl group, specifically, for example, a N-methylcarbamoyl and N-ethylcarbamoyl group.
The xe2x80x9cC4-C9 N-cycloalkylcarbamoyl groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C3-C8 cycloalkyl group and carbamoyl group, specifically, for example, a N-cyclopentylcarbamoyl and N-cyclohexylcarbamoyl group.
The xe2x80x9cC1-C6 alkylsulfonyl groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C1-C6 alkyl group and sulfonyl group, preferably and specifically, for example, a methylsulfonyl group.
The xe2x80x9cC3-C8 (alkoxycarbonyl)methyl groupxe2x80x9d as a substituent for R1 means group consisting of the aforementioned C2-C7 alkoxycarbonyl group and methyl group, preferably and specifically for example, a (methoxycarbonyl)methyl and (ethoxycarbonyl)methyl group.
The xe2x80x9cmono(C1-C6 alkyl)amino groupxe2x80x9d as a substituent for R1 means amino group substituted with one of the aforementioned C1-C6 alkyl group, preferably and specifically, for example, a methylamino and ethyl amino group.
The xe2x80x9cdi(C1-C6 alkyl)amino groupxe2x80x9d as a substituent for R1 means amino group substituted with the same or different two C1-C6 alkyl group aforementioned, preferably and specifically, for example, a dimethylamino; diethylamino, and N-ethyl-N-methylamino group.
Among them, a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C2 C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C2-C4 alkylenoxy group, a methylenedioxy group, a N-phenylcarbamoyl group, an amino group, a mono(C1-C6 alkyl)amino group, and a di(C1-C6 alkyl)amino group can be listed as a preferred specific example for substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1.
Furthermore above substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1 are optionally substituted with one or more of a halogen atom, a hydroxy group, an amino group, a trifluoromethyl group, a C1-C6 alkyl group, or a C1-C6 alkoxy group. The halogen atom, C1-C6 alkyl group, and C1-C6 alkoxy group are the same as defined for the aforementioned substituents for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
In the above formula (I), R1 represents a hydrogen atom, a C1-C6 alkyl group, a C2-C7 alkoxycarbonyl group, a hydroxy group, or a phenyl group, in which the C1-C6 alkyl or phenyl group may be substituted with one or more of a halogen atom, a hydroxy group, a C1-C6 alkyl group, or a C1-C6 alkoxy group, and when j=0, R2 is not a hydroxy group.
The C1-C6 alkyl group and C3-C7 alkoxycarbonyl group for R2 are the same as defined for the aforementioned substituent for the phenyl group, C3-C6 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
The halogen atom, C1-C6 alkyl group, and C1-C6 alkoxy group as substituents for the C1-C6 alkyl or phenyl group in R2 are the same as defined for the aforementioned substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
Among them, a hydrogen atom is a preferred specific example for R2.
In the above formula (I), j represents an integer of 0-2. It is particularly preferred for j to be 0.
In the above formula (I), k represents an integer of 0-2 and m represents an integer of 2-4. It is preferred to use a 2-substituted pyrrolidine in which k is 0 and m is 3, a 3-substituted pyrrolidine in which k is 1 and m is 2, a 3-substituted piperidine in which k is 1 and m is 3, a 4-substituted piperidine in which k is 2 and m is 2, or 3-substituted hexahydroazepine in which k is 1 and m is 4.
n in the above formula (I) represents 0 or 1.
Especially, 3-amidopyrrolidines in which k is 1, m is 2, and n is 0 and 4-(amidomethyl)piperidines in which k is 2, m is 2, and n is 1 can be listed as a particularly preferred example.
R3 in the above formula (I) represents a hydrogen atom or a C1-C6 alkyl group optionally substituted with one or two phenyl groups each of which may be substituted with one or more of a halogen atom, a hydroxy group, a C1-C6 alkyl group, or a C1-C6 alkoxy group.
The C1-C6 alkyl group for R3 is the same as defined for the aforementioned substituents for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, specifically, for example, a methyl, ethyl and propyl group.
The halogen atom, C1-C6 alkyl group, and C1-C6 alkoxy group as substituents for the phenyl group, which is a substituent for C1-C6 alkyl group in R3, are the same as defined for the aforementioned substituents for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
Among them, a hydrogen atom is a preferred specific example for R3.
In the above formula (I), R4 and R5 are the same or different from each other and are a hydrogen atom, a hydroxy group, a phenyl group, or a C1-C6 alkyl group, in which the C1-C6 alkyl group is optionally substituted with one or more of a halogen atom, a hydroxy group, a cyano group, a nitro group, a carboxy group, a carbamoyl group, a mercapto group, a guanidino group, a C3-C8 cycloalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a phenyl group optionally substituted with one or more of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a benzyloxy group, a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C2-C7 alkanoyl group, a C2-C7 alkoxycarbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, a C2-C7 N-alkylcarbamoyl group, a C1-C6 alkylsulfonyl group, an amino group, a mono (C1-C6 alkyl) amino group, a di(C1-C6 alkyl)amino group, or an aromatic heterocyclic group having 1-3 of heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof and optionally condensed with benzene ring, or R4 and R5 taken together form a 3 to 6 membered cyclic hydrocarbon.
The C1-C6 alkyl group for R4 and R5 is the same as defined for the aforementioned substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
The halogen atom, C1-C6 alkoxy group, C1-C6 alkylthio group, C2-C7 alkanoyl group, C2-C7 alkoxycarbonyl group, C2-C7 alkanoyloxy group, C2-C7 alkanoylamino group, C2-C7 N-alkylcarbamoyl group, C1-C6 alkylsulfonyl group, mono(C1-C6 alkyl)amino group, and di(C1-C6 alkyl)amino group as a substituent for the C1-C6 alkyl group in R4 and R5 are the same as defined for the aforementioned substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
The C3-C8 cycloalkyl group and aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof as substituent for the C1-C6 alkyl group in R4 and R5 are the same as defined for the aforementioned group for R1, and the same examples can be listed as preferred specific examples.
The halogen atom, C1-C6 alkyl group, and C1-C6 alkoxy group for the substituent for the phenyl group which is substituent for the C1 -C6 alkyl group in R4 and R5 are the same as defined for the aforementioned substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
The xe2x80x9c3 to 6 membered cyclic hydrocarbonxe2x80x9d consisting of R4, R5, and the adjacent carbon atom includes a cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
Among them, a hydrogen atom and a C1-C6 alkyl group can be listed as a preferred specific example for R4 and R5.
In the above formula (I), p represents 0 or 1, and q represents 0 or 1. It is particularly preferred for both p and q to be 0.
In the above formula (I), G is a group represented by xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR7xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR7xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CSxe2x80x94NHxe2x80x94, xe2x80x94NR7xe2x80x94SO2xe2x80x94, xe2x80x94SO2xe2x80x94NR7xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, or xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94, wherein R7 is a hydrogen atom or a C1-C6 alkyl group, or R7 taken together with R5 represents a C2-C5 alkylene group.
In the above formula, xe2x80x94COxe2x80x94 means a carbonyl group, xe2x80x94SO2xe2x80x94 means a sulfonyl group, and xe2x80x94CSxe2x80x94 means a thiocarbonyl group. Preferred G group is specifically, for example, those represented by the formula xe2x80x94NR7xe2x80x94COxe2x80x94 and xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94.
The C1-C6 alkyl group for R7 are the same as defined for the aforementioned substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
The xe2x80x9cC3-C5 alkylene groupxe2x80x9d consisting of R5 and R7 means C2-C5 straight-chain or branched alkylene group such as a methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, pentamethylene group, and the like, suitably and specifically including a ethylene, trimethylene and tetramethylene group.
A hydrogen atom is a preferred specific example for R7.
In the above formula (I), R6 is a phenyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkenyl group, a benzyl group, or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, in which the phenyl, benzyl, or aromatic heterocyclic group may be condensed with a benzene ring or an aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, to form a condensed ring, and the phenyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring may be substituted with one or more of a halogen atom, a hydroxy group, a mercapto group, a cyano group, a nitro group, a thiocyanato group, a carboxy group, a carbamoyl group, a trifluoromethyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyloxy group, a C1-C6 alkylthio group, a C1-C3 alkylenedioxy group, a phenyl group, a phenoxy group, a phenylamino group, a benzyl group, a benzoyl group, a phenylsulfinyl group, a phenylsulfonyl group, a 3-phenylureido group, a C2-C7 alkanoyl group, a C2-C7 alkoxycarbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, a C2-C7 N-alkylcarbamoyl group, a C1-C6 alkylsulfonyl group, a phenylcarbamoyl group, a N,N-di(C1-C6 alkyl)sulfamoyl group, an amino group, a mono(C1-C6 alkyl) amino group, a di(C1-C6 alkyl)amino group, a benzylamino group, a C2-C7 (alkoxycarbonyl)amino group, a C1-C6 (alkylsulfonyl)amino group, or a bis(C1-C6 alkylsulfonyl)amino group.
The C3-C8 cycloalkyl group, aromatic heterocyclic group having 1-3 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, or a combination thereof, and the condensed ring for R6 are the same as defined for the aforementioned R1, and the same examples can be listed as preferred specific examples.
The xe2x80x9cC3-C8 cycloalkenyl groupxe2x80x9d for R6 means a cyclic alkenyl group such as a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl group, specifically including a 1-cyclopentenyl and 1-cyclohexenyl group.
Among them, a phenyl group, a furyl group, and a thienyl group can be listed as a preferred specific example for R6.
The halogen atom, C1-C6 alkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group, C1-C6 alkylthio group, C1-C3 alkylenedioxy group,C2-C7 alkanoyl group, C2-C7 alkoxycarbonyl group, C2-C7 alkanoyloxy group, C2-C7 alkanoylamino group, C2-C7 N-alkylcarbamoyl group, C1-C6 alkylsulfonyl group, mono(C1-C6 alkyl)amino group, and di(C1-C6 alkyl) amino group as a substituent for the phenyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R6 are the same as defined for the aforementioned substituent for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
The C3-C8 cycloalkyl group as a substituent for R6 is the same as defined for the aforementioned C3-C8 cycloalkyl group for R1, where the same examples can be given for the preferred specific examples.
The xe2x80x9cC3-C8 cycloalkyloxy groupxe2x80x9d as a substituent for R6 means group consisting of the aforementioned C3-C8 cycloalkyl group and oxy group, specifically, for example, a cyclopropyloxy, cyclopentyloxy, and cyclohexyloxy group.
The xe2x80x9cN,N-di(C1-C6 alkyl)sulfamoyl groupxe2x80x9d as a substituent for R6 means sulfamoyl group substituted with the same or different two C1-C6 alkyl group aforementioned, preferably and specifically, for example, a N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-ethyl-N-methylsulfamoyl group.
The xe2x80x9cC2-C7 (alkoxycarbonyl) amino groupxe2x80x9d as a substituent for R6 means group consisting of the aforementioned C2-C7 alkoxycarbonyl group and amino group, specifically, for example, a (methoxycarbonyl)amino and (ethoxycarbonyl)amino group.
The xe2x80x9cC1-C6 (alkylsulfonyl)aminoxe2x80x9d group as a substituent for R6 means group consisting of the aforementioned C1-C6 alkylsulfonyl group and amino group, specifically, for example, a (methylsulfonyl)amino group.
The xe2x80x9cbis(C1-C6 alkylsulfonyl) aminoxe2x80x9d group as a substituent for R6 means amino group substituted with the same or different two C2-C6 alkylsulfonyl group aforementioned, preferably and specifically, for example, a bis(methylsulfonyl)amino group.
Among them, a halogen atom, a mercapto group, a nitro group, a thiocyanato group, a trifluoromethyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a phenyl group, a phenylsulfonyl group, a C2-C7 alkanoylamino group or an amino group can be listed as preferred specific example for substituent f r the phenyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R6.
Furthermore above substituents for the phenyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, benzyl group, aromatic heterocyclic group, or condensed ring in R6 are optionally substituted with one or more of a halogen atom, a cyano group, a hydroxy group, an amino group, trifluoromethyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a mono (C1-C6 alkyl)amino group, or a di(C1-C6 alkyl)amino group.
The halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, a C1-C6 alkylthio group, mono(C1-C6 alkyl)amino group, and di(C1-C6 alkyl)amino group are the same as defined for the aforementioned substituents for the phenyl group, C3-C8 cycloalkyl group, aromatic heterocyclic group, or condensed ring in R1, and the same examples can be listed as preferred specific examples.
The compound represented by the formula (I) above, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C1-C6 alkyl addition salt can be used to prepare a chemokine receptor antagonist preparation of the present invention by formulating the therapeutically effected amount and a carrier and/or diluent into a pharmaceutical composition. Thus, the cyclic amine derivatives shown by the above formula (I), a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C1-C6 alkyl addition salt can be administered orally or by parenterally, for example, intravenously, subcutaneously, intramuscularly, percutaneously or intrarectally.
The oral administration can be accomplished in the form of tablets, pills, granules, powder, solution, suspension, capsules, etc.
The tablets for example can be prepared using a vehicle such as lactose, starch and crystallized cellulose; binder such as carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone; disintegrator such as sodium alginate, sodium bicarbonate and sodium lauryl sulfate, etc.
Pills, powder and granule preparations can be prepared by a standard method using the vehicles mentioned above. Solution or suspension can be prepared by a standard method using glycerin ester such as tricaprylin and triacetin or alcohols such as ethanol. Capsules can be made by charging granules, powder or solution in gelatin, etc.
Subcutaneous, intramuscular or intravenous preparations can be prepared as an injection using aqueous or nonaqueous solution. Aqueous solution for example may include isotonic sodium chloride solution. Nonaqueous solutions may include for example, propyleneglycol, polyethyleneglycol, olive oil, ethyl oleate, etc., and optionally, one can add antiseptics and stabilizers. For injection, one can be sterilized by filtration through a bacterial filter or combination of disinfectant.
Percutaneous administration may be in the form of an ointment or cream, and ointment can be prepared in the standard manner using fatty oils such as castor oil and olive oil, or Vaseline, while creams can be made using fatty oils or emulsifying agent such as diethyleneglycol and sorbitan esters of fatty acid.
For intrarectal administration, one can use standard suppositories using gelatin soft capsules, etc.
The cyclic amine derivatives of the present invention, a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable C1-C6 alkyl addition salt is administered at a dose that varies depending on the type of disease, route of administration, age and sex of patient, and severity of disease, but is likely to be 1-500 mg/day in an average adult.
Preferred specific examples for the cyclic amine compound in the above formula (I) include compound having each substituent as shown in the following Tables 1.1-1.201.
In the Tables 1.1-1.201, xe2x80x9cchiralityxe2x80x9d means configuration of the asymmetric carbon atom on the cyclic amine. xe2x80x9cRxe2x80x9d shows that the asymmetric carbon atom has a R configuration, xe2x80x9cSxe2x80x9d shows that the asymmetric carbon atom has a S configuration, and xe2x80x9c-xe2x80x9d means racemate or that the compound do not have a asymmetric carbon atom on the nitrogen containing ring.
[Table 1.1-Table 1.201]
The present invention can also use acid addition salt of the cyclic amine compound where such acids include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, and the like, as well as organic acids such as maleic acid, citric acid, malic acid, tartaric acid, fumaric acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and the like.
Furthermore, the present invention can also use a C1-C6 alkyl addition salt of the cyclic amine compound, such as 1-(4-chlorobenzyl)-1-methyl-4-[{N-(3-trifluoromethylbenzoyl)glycyl}aminomethyl]piperidinium iodide, where such alkyl include, for example, a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl, 1-ethylbutyl, and the like, suitably specifically including, a methyl and ethyl group. As preferred specific examples for counter anion of the ammonium cation, a halide anion such as fluoride, chloride, bromide or iodide can be listed.
The present invention may use racemates and all possible optically active forms of the compound represented by the above formula (I).
Compound represented by the above general formula (I) can be synthesized by any of the general preparations given below.
A preparation which call for treating one equivalent of a compound represented by the formula (II) below: 
{where R1, R2, R3, j, k, m, and n are the same as defined respectively in the above formula (I)} with 0.1-10 equivalents of a carboxylic acid represented by the formula (III) below: 
{where R4, R5, R6, G, p, and q are the same as defined respectively in the above formula (I)}, or its reactive derivative, either in the absence or presence of solvent.
The reactive derivative for the carboxylic acid in the above formula (III) include highly reactive carboxylic acid derivatives, which are usually used in synthetic organic chemistry, such as acid halides, acid anhydrides, mixed acid anhydrides.
Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent such as molecular sieve, coupling reagent such as dicyclohexylcarbodiimide (DCC), N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide (EDCI or WSC), carbonyldiimidazole (CDI), N-hydroxysuccinimide (HOSu), N-hydroxybenzotriazole (HOBt), benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP(copyright)), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TBTU), 2-(5-norbornene-2,3-dicarboxyimido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), bromotris (pyrrolidino)phosphonium hexafluorophosphate (PyBroP(copyright)), and the like, or base including inorganic salts such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, and the like, amines such as triethylamine, diisopropylethylamine, and pyridine, and the like, or polymer supported bases such as (piperidinomethyl)polystyrene, (morpholinomethyl)polystyrene, (diethylaminomethyl)polystyrene, poly(4-vinylpyridine), and the like.
A preparation which calls for treating 1 equivalent of an alkylating reagent given by the formula (IV) below: 
{where R1, R2, and j are the same as defined respectively in the above formula (I)}; X represents a halogen atom, alkylsulfonyloxy group, or arylsulfonyloxy group), with 0.1-10 equivalents of a compound represented by the formula (V) below: 
{where R3, R4, R5, R6, G, k, m, n, p, and q are the same as defined respectively in the above formula (I)} either in the absence or presence of solvent.
Such reactions can be more smoothly run if a base similar to that used in the above preparation 1 is present. In addition, the reactions in these preparations can also be promoted by iodide such as potassium iodide, sodium iodide, and the like.
In the above formulas (IV), X represents a halogen atom, alkylsulfonyloxy group, arylsulfonyloxy group. Such halogen atoms include preferably chlorine, bromine, and iodine atoms. Suitable specific examples for the alkylsulfonyloxy groups include methylsulfonyloxy, trifluoromethylsulfonyloxy group, and the like. A preferred specific example for the arylsulfonyloxy group includes a tosyloxy group.
A preparation which calls for treating 1 equivalent of an aldehyde represented by the formula (VI) below: 
{where R1 and R2 are the same as defined respectively in the above formula (I); j1 represents 1 or 2} or the formula (VII) below:
R1xe2x80x94CHOxe2x80x83xe2x80x83(VII)
{where R1 is the same as defined in the above formula (I); j represents 0}, with 0.1-10 equivalents of a compound represented by the formula (V) either in the absence or presence of solvent under reductive conditions.
Such reactions are in general called reductive amination reactions and such reductive conditions may be generated by catalytic hydrogenation using a catalyst containing a metal such as palladium, platinum, nickel, rhodium, or the like, using complex hydrides, such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like, boranes, or electrolytic reduction, and the like.
A preparation which call for treating one equivalent of a compound represented by the formula (VIII) below: 
{where R1, R2, R3, R4, R5, R7, j, k, m, n, p and q are the same as defined respectively in the above formula (I)] with 0.1-10 equivalents of a carboxylic acid or sulfonic acid represented by the formula (IX) below:
HOxe2x80x94Axe2x80x94R6xe2x80x83xe2x80x83(IX)
{where R6 is the same as defined in the above formulas (I); xe2x80x9cAxe2x80x9d represents a carbonyl group or sulfonyl group}, or its reactive derivative, either in the absence or presence of solvent.
The reactive derivative for the carboxylic acid or sulfonic acid in the above formula (IX) include highly reactive carboxylic acid or sulfonic acid derivative, which are usually used in synthetic organic chemistry, such as acid halides, acid anhydrides, mixed acid anhydrides.
Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent, coupling reagent, or base which are similar to those used in the above preparation 1.
A preparation which calls for treating 1 equivalent of a compound represented by the above formula (VIII) with 0.1-10 equivalents of a isocyanate or isothiocyanate represented by the formula (X) below:
Zxe2x95x90Cxe2x95x90Nxe2x80x94R6xe2x80x83xe2x80x83(X)
{where R6 is the same as defined in the above formulas (I)}; Z represents a oxygen atom or sulfur atom), either in the absence or presence of solvent.
A preparation which calls for treating 1 equivalent of a compound represented by the formula (XI) below: 
{where R1, R2, R3, R4, R5, j, k, m, n, p and q are the same as defined respectively in the above formula (I)}; xe2x80x9cAxe2x80x9d represents a carbonyl group or sulfonyl group) with 0.1-10 equivalents of an amine represented by the formula (XII) below:
R6xe2x80x94NH2xe2x80x83xe2x80x83(XII)
{where R6 is the same as defined in the above formula (I)}, either in the absence or the presence of solvent.
Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent, coupling reagent, or base which are similar to those used in the above preparation 1.
If the substrates submitted to each of the above preparations contains a substituent which reacts under each reaction condition or is thought to adversely affect the reaction in general in synthetic organic chemistry, that functional group can be protected by a known suitable protecting group followed by the reaction of the above preparations and deprotection using a known procedure to obtain the desired compound.
Furthermore, a compound of the present invention can be prepared by the further conversion of the substituent(s) of the compound, prepared with the above preparations 1-6, using known reactions which are usually used in synthetic organic chemistry, such as alkylation, acylation, reduction, and so on.
Each of the above preparations may use solvents for the reaction such as halogenated hydrocarbons such as dichloromethane, chloroform, and the like, aromatic hydrocarbons such as benzene, toluene, and the like, ethers such as diethyl ether, tetrahydrofuran, and the like, esters such as ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like, alcohols such as methanol, ethanol, isopropyl alcohol, and the like.
The reaction temperature in either of the preparations should be in the range of xe2x88x9278xc2x0 C.-+150xc2x0 C., preferably 0xc2x0 C.-100xc2x0 C. After completion of the reaction, the usual isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired cyclic amine compound represented by the above formula (I). These can be converted into pharmaceutically acceptable acid addition salt or C1-C6 alkyl addition salt by the usual method.
The chemokine receptor antagonist, which contain the cyclic amine compound, its pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable C1-C6 alkyl addition salt of this invention, which inhibits chemokines such as MIP-1xcex1 and/or MCP-1 and the like from action on target cells, are useful as therapeutic agents and/or preventive preparation for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn""s disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, sepsis, and the like, in which tissue infiltration of blood monocytes, lymphocytes, and the like plays a major role in the initiation, progression, and maintenance of the disease.